Fused heteroaryl carboxylic acids as PPAR agonists

Abstract

Fused heteroarylcarboxylic acids of formula (I): wherein R 1 , Ar, A, Y, HET, Q, and T are as defined in the specification; pharmaceutical compositions containing effective amounts of said compounds or their salts are useful for treating PPAR related disorders, such as diabetes, dyslipidemia, obesity and inflammatory disorders.

What is claimed:  
     
         1 . A compound of formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 Ar is (C 3 -C 10 )cycloalkyl, (C 2 -C 10 )heterocyclyl, (C 6 -C 10 )aryl, or (C 1 -C 10 )heteroaryl, wherein each Ar is optionally substituted with one to four substituents selected from Z;  
 A is —CH 2 —, —NH, —O—, or —S—;  
 R 1  is (C 1 -C 8 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 10 )heterocyclyl, (C 6 -C 10 )aryl, or (C 1 -C 10 )heteroaryl; wherein each R 1  is optionally substituted with one to four substituents selected from Z 1 ;  
 Y is selected from the group consisting of —(CH 2 ) n —, —(CH 2 ) n —NR 15 —, —(CH 2 ) n —O—, and —(CH 2 ) n —S—; wherein each n is independently 0, 1, 2, or 3;  
 and R 15  is hydrogen, (C 1 -C 8 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 10 )heterocyclyl, (C 6 -C 10 )aryl, or (C 1 -C 10 )heteroaryl; wherein each R 15  is optionally substituted with one to four substituents selected from Z 2 ;  
 Q is selected from the group consisting of —(CR 2 R 3 ) m —, —(CR 2 R 3 ) m —N 15 —, —N 15 —(CR 2 R 3 ) m —, (CR 2 R 3 ) m —O—, —O—(CR 2 R 3 ) m —, —S—(CR 2 R 3 ) m —, and —(CR 2 R 3 ) m —S—; wherein each m is independently 1, 2, 3, 4, 5, or 6;  
                     
 is a fused (C 6 -C 12 )heteroaryl optionally substituted one to four substituents selected from Z 3 , wherein Z 3  may be in any ring of the fused (C 6 -C 12 )heteroaryl, having the formula:  
                     
 wherein the dotted lines are optional double bonds such that said fused (C 6 -C 12 )heteroaryl is aromatic;  
 Each of X 1 , X 2 , W 1 , W 2 , W 3 , W 4 , B 1 , B 2 , B 3 , B 4 , D 1 , D 2 , D 3  and D 4  are independently ═CH— or ═N—;  
 At least one of X 1 , X 2 , B 1 , B 2 , B 3 , and B 4  must be ═N—;  
 At least one of W 1 , W 2 , W 3 , W 4 , D 1 , D 2 , D 3  and D 4  must be ═N—;  
 Wherein each --c is a point of attachment to the group —Y— and each ---d is a point of attachment to the group —Q—;  
 Each of Z, Z 1 , Z 2 , and Z 3  are selected from the group consisting of: 
 (c) H, F, Cl, Br, I, CF 3 , or CN;  
 (d) (C 1 -C 8 )alkyl optionally substituted with one to four substituents independently selected from R 7 ;  
 (c) —C(═O)—R 4  {wherein R 4  is selected from the group consisting of H, OH, CF 3 , (C 1 -C 8 )alkyl, (C 1 -C 8 )alkyl-O—, (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkyl-O—; (C 2 -C 10 )heterocyclyl, (C 2 -C 10 )heterocyclyl-O—; (C 6 -C 10 )aryl, (C 6 -C 10 )aryl-O—, (C 1 -C 10 )heteroaryl, and (C 1 -C 10 )heteroaryl-O—};  
 (d) —C(═O)—NR 5 R 6  {wherein R 5  is H or (C 1 -C 8 )alkyl; and wherein R 6  is selected from the group consisting of H, (C 1 -C 8 )alkyl, —CH 2 —(C═O)—O—(C 1 -C 8 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 10 )heterocyclyl, (C 6 -C 10 )aryl, and (C 1 -C 10 )heteroaryl};  
 (j) (C 3 -C 10 )cycloalkyl, (C 2 -C 10 )heterocyclyl, (C 6 -C 10 )aryl, or (C 1 -C 10 )heteroaryl;  
 (k) NR 9 R 10  {wherein R 9  is independently H or (C 1 -C 8 )alkyl; R 10  is selected from the group consisting of —C(═O)—O—C(CH 3 ) 3 , (C 1 -C 8 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 10 )heterocyclyl, (C 6 -C 10 )aryl, and (C 1 -C 10 )heteroaryl; or R 9  and R 10  may optionally be taken together with the nitrogen to which they are attached to form a 5 to 8-membered heteroaryl or heterocyclyl ring};  
 (l) R 11 —O— {wherein R 11  is selected from the group consisting of (C 1 -C 8 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 10 )heterocyclyl, (C 6 -C 10 )aryl, and (C 1 -C 10 )heteroaryl};  
 (m) R 12 —SO p — {wherein R 12  is selected from the group consisting of (C 1 -C 8 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 10 )heterocyclyl, (C 6 -C 10 )aryl, and (C 1 -C 10 )heteroaryl; and wherein p is 0, 1, or 2}; and  
 (n) R 13 R 14 N—SO q — {wherein R 13  is H or (C 1 -C 8 )alkyl; R 14  is (C 1 -C 8 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 10 )heterocyclyl, (C 6 -C 10 )aryl, or (C 1 -C 10 )heteroaryl; or R 13  and R 14  may optionally be taken together with the nitrogen to which they are attached to form a 5 to 8-membered heteroaryl or heterocyclyl ring; and wherein q is 1 or 2};  
 
 Each of R 2  and R 3  is independently (a) H; (b) (C 1 -C 8 )alkyl optionally substituted with one to four substituents independently selected from R 7 ; (c) COOH; or (d) (C 6 -C 10 )aryl optionally substituted with one to four substituents independently selected from R 8 ;  
 Wherein each of R 7  and R 8  are independently selected from the group consisting of: 
 (g) F, Cl, Br, I, CN, CF 3 , or NO 2 ;  
 (h) —NR 9 R 10  {wherein R 9  is independently H or (C 1 -C 8 )alkyl; R 10  is selected from the group consisting of —C(═O)—O—C(CH 3 ) 3 , (C 1 -C 8 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 10 )heterocyclyl, (C 6 -C 10 )aryl, and (C 1 -C 10 )heteroaryl; or R 9  and R 10  may optionally be taken together with the nitrogen to which they are attached to form a 5 to 8-membered heteroaryl or heterocyclyl ring};  
 (i) R 11 —O— {wherein R 11  is selected from the group consisting of (C 1 -C 8 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 10 )heterocyclyl, (C 6 -C 10 )aryl, and (C 1 -C 10 )heteroaryl};  
 (j) R 12 —SO p — {wherein R 12  is selected from the group consisting of (C 1 -C 8 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 10 )heterocyclyl, (C 6 -C 10 )aryl, and (C 1 -C 10 )heteroaryl; and wherein p is 0, 1, or 2}; and  
 (k) R 13 R 14 N—SO q — {wherein R 13  is H or (C 1 -C 8 )alkyl; R 14  is (C 1 -C 8 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 10 )heterocyclyl, (C 6 -C 10 )aryl, or (C 1 -C 10 )heteroaryl; or R 13  and R 14  may optionally be taken together with the nitrogen to which they are attached to form a 5 to 8-membered heteroaryl or heterocyclyl ring; and wherein q is 1 or 2};  
 
 (l) T is selected from the group consisting of —(C═O)—OH, —(C═O)—OR 15 , —(C═O)—OM {wherein M is an alkali metal or alkaline earth metal}, tetrazolyl, thiazolidinyl, —SO 2 —NH—R 15 , —NH—SO 2 —R 15 , —(C═O)—NH—SO 2 —R 15 , and other acid prodrug or isosteres thereof;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The compound according to  claim 1  wherein  
       
         
           
           
               
               
           
         
       
       is a fused (C 6 -C 12 )heteroaryl optionally substituted one to four substituents selected from Z 3 , wherein Z 3  may be in any ring of the fused (C 6 -C 12 )heteroaryl, having the formula:  
       
         
           
           
               
               
           
         
       
       selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . The compound according to  claim 1  wherein  
       
         
           
           
               
               
           
         
       
       is a fused (C 6 -C 12 )heteroaryl optionally substituted one to four substituents selected from Z 3 , wherein Z 3  may be in any ring of the fused (C 6 -C 12 )heteroaryl, having the formula:  
       
         
           
           
               
               
           
         
       
       selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         4 . The compound according to  claim 1  wherein said Ar is phenyl.  
     
     
         5 . The compound according to  claim 1  wherein said A is —O—.  
     
     
         6 . The compound according to  claim 1  wherein said R 1  is (C 1 -C 8 )alkyl.  
     
     
         7 . The compound according to  claim 1  wherein said R 1  is (C 6 -C 10 )aryl.  
     
     
         8 . The compound according to  claim 1  wherein said Q is —(CR 2 R 3 ) m —, m is 2 or 3, and each of R 2  and R 3  is hydrogen or (C 1 -C 8 )alkyl.  
     
     
         9 . The compound according to  claim 1  wherein said Q is —(CR 2 R 3 ) m —NH—, m is 1 or 2, and each of R 2  and R 3  is hydrogen or unsubstituted (C 1 -C 8 )alkyl.  
     
     
         10 . The compound according to  claim 1  wherein said Q is —(CR 2 R 3 ) m —O—, m is 1 or 2, and each of R 2  and R 3  is hydrogen or unsubstituted (C 1 -C 8 )alkyl.  
     
     
         11 . The compound according to  claim 1  wherein said Q is —(CR 2 R 3 ) m —S—, m is 1 or 2, and each of R 2  and R 3  is hydrogen or unsubstituted (C 1 -C 8 )alkyl.  
     
     
         12 . The compound according to  claim 1  wherein said T is —(C═O)—OH.  
     
     
         13 . The compound according to  claim 1  wherein said T is selected from the group consisting of tetrazolyl, thiazolidinyl, —SO 2 —NH—R 15 , —NH—SO 2 —R 15 , —(C═O)—NH—SO 2 —R 15 , and other acid prodrug or isosteres thereof.  
     
     
         14 . The compound according to  claim 1  wherein said Z 3  is selected from the group consisting of F, Cl, Br, or I.  
     
     
         15 . The compound according to  claim 1  wherein said Z 3  is (C 1 -C 8 )alkyl.  
     
     
         16 . The compound according to  claim 1  wherein said Y is —(CH 2 ) n —O— and n is 1, 2, or 3.  
     
     
         17 . The compound according to  claim 1  wherein said Y is —(CH 2 ) n —NR 15 —, wherein R 15  is hydrogen, (C 1 -C 8 )alkyl or (C 3 -C 10 )cycloalkyl, and n is 1, 2, or 3.  
     
     
         18 . The compound according to  claim 1  wherein said Y is —(CH 2 ) n — and n is 1, 2, or 3.  
     
     
         19 . The compound according to  claim 1  wherein said Y is —(CH 2 ) n —S— and n is 1, 2, or 3.  
     
     
         20 . The compound according to  claim 1  selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and the pharmaceutically acceptable salts thereof.  
     
     
         21 . A method of treating non-insulin dependent diabetes mellitus in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a fused heteroaryl compound according to  claim 1 .  
     
     
         22 . The method of treating non-insulin dependent diabetes mellitus according to  claim 21  wherein said mammal has an impaired glucose tolerance.  
     
     
         23 . A method of treating polycystic ovarian syndrome in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a fused heteroaryl compound according to  claim 1 .  
     
     
         24 . A method of treating obesity in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a fused heteroaryl compound according to  claim 1 .  
     
     
         25 . A method of reducing body weight in an obese mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a fused heteroaryl compound according to  claim 1 .  
     
     
         26 . A method of treating hyperglycemia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a fused heteroaryl compound according to  claim 1 .  
     
     
         27 . A method of treating hyperlipidemia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a fused heteroaryl compound according to  claim 1 .  
     
     
         28 . A method of treating hypercholesteremia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a fused heteroaryl compound according to  claim 1 .  
     
     
         29 . A method of treating atherosclerosis in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a fused heteroaryl compound according to  claim 1 .  
     
     
         30 . A method of treating hypertriglyceridemia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a fused heteroaryl compound according to  claim 1 .  
     
     
         31 . A method of treating hyperinsulinemia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a fused heteroaryl compound according to  claim 1 .  
     
     
         32 . A method of treating a patient suffering from abnormal insulin and/or evidence of glucose disorders associated with circulating glucocorticoids, growth hormone, catecholamines, glucagon, or parathyroid hormone, comprising administering to said patient a therapeutically effective amount of a fused heteroaryl compound according to  claim 1 .  
     
     
         33 . A method of treating insulin resistance syndrome in humans comprising administering to a patient in need of treatment a therapeutically effective amount of a fused heteroaryl compound according to  claim 1 .  
     
     
         34 . A method of treating PPAR-related disorders in humans comprising administering to a patient in need of treatment a therapeutically effective amount of a fused heteroaryl compound according to  claim 1 .  
     
     
         35 . A method of modulating PPAR activity in a mammal, comprising administering to a mammal a therapeutically effective amount of a fused heteroaryl compound according to  claim 1 .  
     
     
         36 . A method of lowering blood glucose in a mammal, comprising administering to a mammal an amount of a fused heteroaryl compound according to  claim 1  effective to lower blood glucose levels.  
     
     
         37 . A method of modulating fat cell differentiation in a mammal, comprising administering to a mammal a therapeutically effective amount of a fused heteroaryl compound according to  claim 1 .  
     
     
         38 . A method of modulating processes mediated by PPAR in a mammal, comprising administering to a mammal a therapeutically effective amount of a fused heteroaryl compound according to  claim 1 .  
     
     
         39 . The method of modulating processes mediated by PPAR in a mammal according to  claim 39 , wherein said fused heteroaryl compound according to  claim 1  is administered to said mammal in combination with at least one compound selected from the group consisting of α-glucosidase inhibitors, aldose reductase inhibitors, biguanide preparations, statin base compounds, squalene synthesis inhibitors, fibrate base compounds, LDL catabolism promoters and angiotensin-converting enzyme inhibitors.  
     
     
         40 . A method of increasing insulin sensitivity in mammals, comprising administering to a mammal a therapeutically effective amount of a fused heteroaryl compound according to  claim 1 .  
     
     
         41 . A composition comprising at least one modulator of PPAR according to  claim 1  and a pharmaceutically acceptable carrier thereof.  
     
     
         42 . A composition according to  claim 40  further comprising at least one compound selected from the group consisting of α-glucosidase inhibitors, aldose reductase inhibitors, biguanide preparations, statin base compounds, squalene synthesis inhibitors, fibrate base compounds, LDL catabolism promoters and angiotensin-converting enzyme inhibitors.